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Selective inhibition of JNK with a peptide inhibitor attenuates pain hypersensitivity and tumor growth in a mouse skin cancer pain model.
Cancer pain significantly affects the quality of cancer patients, and current treatments for this pain are limited. C-Jun N-terminal kinase (JNK) has been implicated in tumor growth and neuropathic pain sensitization. We investigated the role of JNK in cancer pain and tumor growth in a skin cancer pain model. Injection of luciferase-transfected B16-Fluc melanoma cells into a hindpaw of mouse induced robust tumor growth, as indicated by increase in paw volume and fluorescence intensity. Pain hypersensitivity in this model developed rapidly (<5 days) and reached a peak in 2 weeks, and was characterized by mechanical allodynia and heat hyperalgesia. Tumor growth was associated with JNK activation in tumor mass, dorsal root ganglion (DRG), and spinal cord and a peripheral neuropathy, such as loss of nerve fibers in the hindpaw skin and induction of ATF-3 expression in DRG neurons. Repeated systemic injections of D-JNKI-1 (6 mg/kg, i.p.), a selective and cell-permeable peptide inhibitor of JNK, produced an accumulative inhibition of mechanical allodynia and heat hyperalgesia. A bolus spinal injection of D-JNKI-1 also inhibited mechanical allodynia. Further, JNK inhibition suppressed tumor growth in vivo and melanoma cell proliferation in vitro. In contrast, repeated injections of morphine (5 mg/kg), a commonly used analgesic for terminal cancer, produced analgesic tolerance after 1 day and did not inhibit tumor growth. Our data reveal a marked peripheral neuropathy in this skin cancer model and important roles of the JNK pathway in cancer pain development and tumor growth. JNK inhibitors such as D-JNKI-1 may be used to treat cancer pain.
Activating Transcription Factor 3/metabolism, Analgesics, Opioid/pharmacology, Animals, Cell Line, Tumor, Cell Proliferation/drug effects, Disease Models, Animal, Enzyme Inhibitors/pharmacology, Enzyme Inhibitors/therapeutic use, Hyperalgesia/drug therapy, Hyperalgesia/enzymology, JNK Mitogen-Activated Protein Kinases/antagonists & inhibitors, JNK Mitogen-Activated Protein Kinases/metabolism, Male, Melanoma/complications, Melanoma/drug therapy, Mice, Mice, Inbred C57BL, Morphine/pharmacology, Pain/drug therapy, Pain/enzymology, Pain Measurement, Peptides/pharmacology, Peptides/therapeutic use, Peripheral Nervous System Diseases/enzymology, Peripheral Nervous System Diseases/etiology, Sensory Receptor Cells/cytology, Sensory Receptor Cells/drug effects, Skin Neoplasms/complications, Skin Neoplasms/drug therapy
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